Population-based genetic effects for developmental stuttering

• Published in: HGG advances Vol. 3; no. 1; p. 100073
• Main Authors: Polikowsky, Hannah G., Shaw, Douglas M., Petty, Lauren E., Chen, Hung-Hsin, Pruett, Dillon G., Linklater, Jonathon P., Viljoen, Kathryn Z., Beilby, Janet M., Highland, Heather M., Levitt, Brandt, Avery, Christy L., Mullan Harris, Kathleen, Jones, Robin M., Below, Jennifer E., Kraft, Shelly Jo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.01.2022; Elsevier
• Subjects: complex trait; genome-wide assocation study; population-study; stuttering; genome-wide assocation study; stuttering; population-study; complex trait
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2021.100073

Despite a lifetime prevalence of at least 5%, developmental stuttering, characterized by prolongations, blocks, and repetitions of speech sounds, remains a largely idiopathic speech disorder. Family, twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; however, its complex mode of inheritance combined with thus-far underpowered genetic studies contribute to the challenge of identifying and reproducing genes implicated in developmental stuttering susceptibility. We conducted a trans-ancestry genome-wide association study (GWAS) and meta-analysis of developmental stuttering in two primary datasets: The International Stuttering Project comprising 1,345 clinically ascertained cases from multiple global sites and 6,759 matched population controls from the biobank at Vanderbilt University Medical Center (VUMC), and 785 self-reported stuttering cases and 7,572 controls ascertained from The National Longitudinal Study of Adolescent to Adult Health (Add Health). Meta-analysis of these genome-wide association studies identified a genome-wide significant (GWS) signal for clinically reported developmental stuttering in the general population: a protective variant in the intronic or genic upstream region of SSUH2 (rs113284510, protective allele frequency = 7.49%, Z = −5.576, p = 2.46 × 10−8) that acts as an expression quantitative trait locus (eQTL) in esophagus-muscularis tissue by reducing its gene expression. In addition, we identified 15 loci reaching suggestive significance (p < 5 × 10−6). This foundational population-based genetic study of a common speech disorder reports the findings of a clinically ascertained study of developmental stuttering and highlights the need for further research. Despite overwhelming evidence in support of strong genetic influence, the genetic etiology of developmental stuttering has remained elusive. This study reveals genome-wide significant and suggestively significant signals for clinically ascertained stuttering cases in the general population, laying essential groundwork for further research into identification of common stuttering susceptibility variants.